Pharmaceutical composition with gastric residence and controlled release

ABSTRACT

The invention concerns a pharmaceutical composition with gastric residence and controlled release, characterized in that it comprises two or three layers and contains (a) an active principle associated with a excipient modifying its release; (b) a system generating carbon dioxide in a swelling polymer hydrophilic matrix; (a) and (b) capable of being included in a common layer or in separate layers.

The present invention relates to controlled-release pharmaceuticalcompositions with gastric residence.

Attempts are most frequently made to administer medicinal productsorally. However, oral administration is occasionally made difficult whenthe active principle is of low bioavailability.

The term “bioavailability” means herein the fraction of active principlewhich is absorbed from its pharmaceutical form and which arrives in theplasma.

Other active principles are absorbed and may thus be administeredorally, but their absorption is incomplete and occasionally irregular.Some other active principles are absorbed well from fast-releasepharmaceutical forms, the active principle then being released in lessthan half an hour, but are less well absorbed from sustained-releasepharmaceutical forms.

Such a low and irregular bioavailability may be the result of severalfactors. Among these, mention may be made of low solubility or very slowdissolution of the active principle, chemical or enzymatic degradationof the active principle in the gastrointestinal tract or slow orincomplete absorption of the active principle.

Specifically, a certain number of active principles, although beingsufficiently soluble, are poorly absorbed in the colon or less wellabsorbed at this level than in the upper sections of the smallintestine, namely the duodenum, the jejunum and the ileum.

Furthermore, a sustained-release form is useful for many medicinalproducts, for example to allow a less frequent administration: once aday instead of twice a day, or twice a day instead of 3 times a day.

When the active principle is absorbed slowly or incompletely in thelower regions of the gastrointestinal tract, it becomes difficult todesign a sustained-release form, which should typically release theactive principle over 12 to 16 hours. The problem becomes all the moredifficult if there is a window of absorption, i.e. if the activeprinciple is absorbed well only in a portion of the gastrointestinaltract. For example, the active principle may be absorbed well only inthe duodenum and the jejunum. Specifically, a sustained-releasepharmaceutical form requires a release time of at least 8 hours, whichis not achieved in the case of an active principle which is absorbedessentially in the upper sections of the small intestine. This is theproblem which the Applicant proposes to solve.

The present invention is thus directed toward slowing down the speed ofgastrointestinal transit and thus of increasing the time available forabsorption in the upper sections of the small intestine and morespecifically the duodenum, the jejunum and the ileum, while at the sametime controlling the release profile.

The invention thus consists of a pharmaceutical composition with gastricresidence, characterized in that it comprises two or three layers and inthat it comprises.

-   (a) an active principle combined with an excipient which modifies    its release,-   (b) a carbon dioxide-generating system in a swelling hydrophilic    polymer matrix.

The two- or three-layer tablets made from the various combinations of(a) and (b) form part of the invention, (a) and (b) possibly beingincluded in the same layer [(a)+(b)] or in separate layers [(a)] and[(b)]. The redundant layers [(a)], [(b)] or [(a)+(b)] in the same tabletmay have different compositions and dimensions.

Compositions which also form part of the invention are compositions withgastric residence containing two or three layers comprising (a) and (b),characterized in that they comprise a soluble and/or erodable layer. Thetablet may thus comprise a layer [(a)+(b)] and a soluble and/or erodablelayer to give a two-layer tablet, or alternatively a soluble and/orerodable layer coated with two outer layers [(a)+(b)] to give athree-layer tablet.

This embodiment makes it possible, like all the compositions accordingto the invention, to obtain a gradual increase in the contact areabetween the tablet and the liquids contained in the stomach, so as totend toward a zero-order dissolution profile, that is to say acontrolled-release profile.

The compositions according to the invention are characterized in that,on contact with the gastric juices, the layer(s) [(b)] or [(a)+(b)]increase in volume by virtue of the swelling of the hydrophilic polymermatrix and the immediate production of carbon dioxide. In this way,flotation is obtained quickly and the gastric residence time obtained islarge.

The pharmaceutical compositions according to the invention may beuseful, for example, for benzamides and α₁-antagonists, and also thefollowing active principles: captopril, furosemide, ursodeoxycholicacid, amoxicillin, (+)-α-aminomethyl-2-methoxysulfonamidobenzenemethanol(disclosed in patent application EP 842 148 in Example 3.6) or3′-(2-amino-1-hydroxyethyl)-4′-fluoromethane-sulfonanilide (NS 49).

The benzamides are, in particular, metoclopramide, veralipride,alizapride, clebopride and more particularly amisulpride, tiapride andsulpiride, and salts thereof.

The α₁-antagonists are, in particular, terazosine and alfuzosine andsalts thereof, in particular alfuzosine hydrochloride. They are intendedespecially for treating benign hypertrophy of the prostate.

Captopril is used in particular for treating hypertension, furosemide isused as a diuretic, amoxicillin and its salts are used as antibiotics,and ursodeoxycholic acid and its salts are used for treatingcholelithiasis, liver disorders and syphilis.

For the purposes of the present invention, the various enantiomers ordiastereoisomers of the various active principles or families of activeprinciples (benzamides, α₁-antagonists) are also covered, includingmixtures thereof, in particular racemic mixtures thereof, and also saltsthereof.

Among the active principles that are more particularly suitable for thecompositions according to the invention, mention may be made ofamisulpride (D)-tartrate, (S)-(−)-amisulpride, (S)-(−)-amisulpride(D)-tartrate, tiapride hydrochloride, alfuzosine hydrochloride and3′-(2-amino-1-hydroxyethyl)-4′-fluoromethanesulfonanilide hydrochloride.

FIG. 1 shows three embodiments of the invention with variousarrangements of (a) and (b).

FIG. 2 represents the dissolution profile of tiapride hydrochlorideformulated in a three-layer tablet according to the invention.

The main function of the carbon dioxide-generating system is to formcarbon dioxide in the form of bubbles. These bubbles contribute towardrapidly bringing and then maintaining the pharmaceutical composition ofthe invention at the surface of the liquids contained in the stomach.

A carbon dioxide-generating system which is suitable in a pharmaceuticalcomposition according to the invention generally comprises at least onecarbon dioxide-generating agent. The carbon dioxide-generating agent isusually an alkali metal carbonate or an alkaline-earth metal carbonate,such as calcium carbonate, or an alkali metal bicarbonate, preferablysodium bicarbonate.

Such a carbon dioxide-generating system, consisting solely of a carbondioxide-generating agent, does not begin to form carbon dioxide bubblesuntil it has been placed in contact with a medium at acidic pH,generally that of the stomach.

In order to accelerate the formation of carbon dioxide bubbles and thusimprove the flotation of the pharmaceutical composition with gastricresidence of the invention, it is preferred to use a pH-independentcarbon dioxide-generating system. Such a system may comprise a carbondioxide-generating agent such as those mentioned above, along with atleast one acidic compound chosen from the group consisting ofmonocarboxylic acids such as lactic acid, polycarboxylic acids andpartial salts of polycarboxylic acids. Acidic compounds which may bementioned more particularly include tartaric acid, maleic acid, malonicacid, malic acid, fumaric acid, succinic acid, adipic acid and citricacid and partial salts thereof, such as monosodium citrate.

In such a carbon dioxide-generating system, the content of acidiccompound is generally chosen such that the number of moles of the saidacidic compound relative to the number of moles of the said carbondioxide-generating agent is from 0.7 to 1.4 times the stoichiometry.

However, if the active principle or any other component forming part ofthe formulation of the composition according to the invention is ofbasic nature, it may be consequently necessary to increase the contentof acidic compound.

The hydrophilic polymers which are suitable for forming a swellinghydrophilic polymer matrix may be chosen from:

-   natural polysaccharides such as alginates, xanthan gum, guar gum,    gum arabic or carob gum,-   semi-synthetic polysaccharides, in particular cellulose derivatives    such as methylhydroxyethyl-cellulose, cellulose,    carboxymethylcellulose and its salts such as sodium    carboxymethylcellulose or calcium carboxymethylcellulose,    hydroxypropylcellulose or hydroxypropylmethylcellulose, or-   synthetic hydrophilic polymers such as    -   polyvinylpyrrolidones,    -   polymers derived from acrylic acid and methacrylic acid and        salts thereof, such as polyacrylates, in particular those sold        under the brand name Carbopol®, or    -   aminoacid polymers such as polylysines.

Among the natural polysaccharides that are preferred are alginates andxanthan gum.

Among the semi-synthetic polysaccharides that are preferred arehydroxypropylcellulose and hydroxypropylmethylcellulose.

The swelling hydrophilic polymer matrix may consist of a singlehydrophilic polymer mentioned above or a mixture of several of them,chosen from the same family of hydrophilic polymers and preferably up tothree of them.

In the context of the present invention, the families of hydrophilicpolymers are defined by the following list:

-   natural polysaccharides,-   cellulose derivatives,-   polyvinylpyrrolidones,-   polymers derived from acrylic acid and methacrylic acid and salts    thereof,-   aminoacid polymers.

Among the mixtures which may be mentioned in particular are mixtures ofhydroxypropylcellulose and of hydroxypropylmethylcellulose and mixturesof hydroxypropylmethylcelluloses of different molecular weights.

One mixture which is particularly preferred consists ofhydroxypropylmethylcelluloses of different molecular weights.

In order to promote a rapid increase in the volume of the pharmaceuticalcomposition, with the hydrophilic polymers mentioned above, it ispossible to use hydrophilic products and/or excipients capable ofpromoting the hydration of the swelling polymer matrices. Hydrophilicdiluents such as lactose, mannitol, sorbitol or microcrystallinecellulose may be used for this purpose. Substances which allow fasterwetting of the swelling polymer matrix or matrices may also beintroduced, thereby facilitating the interaction between the componentsof this or these layers and the biological fluids. Examples of suchsubstances are sodium lauryl sulfate, sodium ricinoleate, sodiumtetradecylsulfate, sodium dioctyl sulfosulfonate, ketomagrocol,poloxamer, polysorbates or any other pharmacologically acceptablesurfactant.

Two cases may be distinguished in the choice of excipients which modifythe release of the active principle included in (a):

-   When the active principle and the carbon dioxide-generating system    are in the same layer [(a)+(b)], the hydrophilic polymer(s) which    form(s) the swelling hydrophilic matrix or matrices act(s) as    modifiers of the release of the active principle. Consequently, a    specific excipient which modifies the release of the active    principle is not added to the swelling hydrophilic polymers.-   When the active principle is in a layer [(a)] comprising no (b), the    excipients modifying the release of the active principle are either    hydrophilic polymers or lipid substances which may form a matrix, or    a combination of both.

The hydrophilic polymers which may modify the release of the activeprinciple may be chosen from those listed above as hydrophilic polymersforming a swelling matrix, to which may be added ethylcellulose,methylcellulose and acrylic copolymers among them those sold under thebrand name Eudragit®.

The lipid substances may be chosen from hydrogenated castor oil,beeswax, carnauba wax, glyceryl trimyristate, glyceryl trilaurate,glyceryl tristearate, cetyl palmitate and glyceryl behenate.

The soluble and/or erodable material, one layer of which may consist of[lacuna], may be chosen from: soluble diluents such as lactose,mannitol, sorbitol, xylitol or polyalcohols, occasionally mixed withother hydrophilic diluents such as microcrystalline cellulose. Polymerssuch as hydroxyethylcellulose, carboxymethylcellulose, alginate,albumin, soluble starch or gelatin may be incorporated into this solubleand/or erodable layer up to a percentage of 25% by weight to control therate of erosion and/or dissolution.

The technical preparation of the tablets may lead to the introduction:

-   of lubricants such as magnesium stearate, sodium stearylfumarate,    stearic acid, glyceryl monostearate, polyoxyethylene glycols with a    molecular weight of from 400 to 7 000 000, hydrogenated castor oil,    glyceryl behenate and mono-, di- or trisubstituted glycerides,-   glidants such as colloidal silica or any other silica, and-   binders, buffers and absorbers, and also any other pharmaceutically    acceptable additive.

According to preferred embodiments, the compositions of the inventionmay take the following different forms:

(1) A two-layer tablet, the first layer comprising the active principleand an excipient which modifies its release, and the second layercomprising a carbon dioxide generator in a swelling polymer matrix.

This type of tablet is represented in FIG. 1(i).

(2) A three-layer tablet, the first layer comprising the activeprinciple and an excipient which modifies its release, and the two outerlayers comprising a carbon dioxide generator in a swelling polymermatrix. The composition and size of the two outer layers may beidentical or different.

This type of tablet is represented in FIG. 1(ii).

(3) A three-layer tablet, the outer layers comprising the activeprinciple combined with an excipient which modifies its release and acarbon dioxide generator, the whole in a swelling polymer matrix, andthe inner layer consisting of a soluble and/or erodable material andoptionally of a carbon dioxide generator. The composition and size ofthe two outer layers may be identical or different.

This type of tablet is represented in FIG. 1 (iii).

The tablets of the invention may be produced in the following way:powders and/or granules are mixed together using the current productiontechniques, and thus with a production process which may be immediatelytransferred to the industrial scale.

The two-layer or three-layer pharmaceutical tablet is obtained accordingto tableting processes that are widely used by and known to thoseskilled in the art.

For example, the tablets may be produced using rotary presses capable ofproducing “multi-layer” tablets.

Normally, the working tableting force ranges from 7 to 50 kN (orkilonewtons) and two-layer or three-layer tablets are obtained incylindrical, lenticular, spheroidal or ovoidal shape, making them easyto administer and swallow.

Depending on the amount of active principle which is conveyed, eachlayer of the tablet may have a different thickness ranging from 0.2 mmto 8 mm, but preferably from 1 mm to 4 mm.

A coating made of polymer materials may also be applied to thepharmaceutical composition for the purpose of providing a simpleprotection of the pharmaceutical composition. In this case, the coatingshould be soluble in acid and neutral solution.

The coating may be applied by conventional methods known to thoseskilled in the art, using organic or aqueous solutions.

The contents of the various compounds constituting a pharmaceuticalcomposition according to the invention are generally chosen such thatthe relative density of this composition in the stomach is less than1.00.

A pharmaceutical composition according to the invention usuallycomprises from 0.5% to 70% and preferably from 2% to 60% by weight ofactive principle, from 10% to 80% and preferably from 15% to 60% byweight of excipient which modifies the release of the active principle,from 10% to 75% and preferably from 15% to 60% by weight of at least onehydrophilic polymer and from 2.5% to 50% and preferably from 10% to 40%by weight of carbon dioxide-generating agent, the percentages beingexpressed relative to the total weight of the said composition.

The examples which follow illustrate the present invention.

EXAMPLE 1 Sustained-Release Floating Tablet Containing 3 Layers ofTiapride Hydrochloride

Two granules are prepared. For granule 1, Methocel® K100M, Avicel® PH102and tartaric acid are dry-mixed and then granulated with water in agranulating blender and the granules obtained are then dried. The othercomponents, magnesium stearate, Aerosile® 200 and monosodium carbonateare then dry-added and mixed. For granule 2, tiapride hydrochloride,Methocel® and Avicel® are dry-mixed and are then granulated with waterin a granulating blender and the granules obtained are then dried.Magnesium stearate and Aerosile® are dry-added and mixed. 3-layertablets are prepared, containing 250 mg of granule 1 in the first outerlayer, 280 mg of granule 2 in the inner layer, which contains 100 mg ofbase tiapride in hydrochloride form, and 200 mg of granule 1 in thesecond outer layer.

Granule 1: outer layers 1 and 3 Methocel ® K100M¹ 45.6% Avicel ® PH102²15.3% Tartaric acid 17.9% Monosodium carbonate 20.0% Magnesium stearate 1.0% Aerosil ® 200³  0.2% 100.0%  Granule 2: inner layer 2 Tiapridehydrochloride 39.6% Methocel ® K100M 41.6% Avicel ® PH101 17.6%Aerosil ® 200  0.2% Magnesium stearate  1.0% 100.0% ¹hydroxypropylmethylcellulose sold by Dow Chemical Co. ²microcrystallinecellulose sold by Edward Mendell Co. ³colloidal silica sold by thecompany Degussa

The in vitro dissolution is tested according to the following method:

The vane machine described by the European Pharmacopea is used. Thestirring speed is 200 rpm. The UV absorbance is read continuously, bymeans of withdrawal using a peristaltic pump. The percentage ofdissolved tiapride is determined as a function of time, by comparing theUV absorbance at 288 nm of the sample with that of a tiapridehydrochloride standard with a concentration of 0.222 mg/ml in thedissolution medium. The dissolution medium consists of 1000 ml of 0.01 Mhydrochloric acid. The results are given in FIG. 2.

A controlled release of the tiapride hydrochloride is obtained.

EXAMPLE 2 Sustained-Release Floating 3-Layer Tablet of NS 49 inHydrochloride Form

2 granules are prepared. Granule 1 is identical to that of the aboveexample. Granule 2 is as described below. Three-layer tablets areprepared, containing 150 mg of granule 1 in the first outer layer, 100mg of granule 2 in the inner layer, which contains 2 mg of NS 49 inhydrochloride form, and 100 mg of granule 1 in the 2nd outer layer.

Granule 2: inner layer 2 NS 49 hydrochloride  2.0% Methocel ® K100M45.0% Avicel ® PH101 51.8% Aerosil ® 200  0.2% Magnesium stearate  1.0%100.0% 

1. A controlled-release pharmaceutical composition with gastricresidence comprising two or three layers and consisting essentially of:(a) an active principle combined with an excipient which modifies itsrelease, (b) a carbon dioxide-generating system in a swellinghydrophilic polymer matrix consisting of a hydrophilic polymer chosenfrom the following families of hydrophilic polymers: naturalpolysaccharides, cellulose derivatives, polyvinylpyrrolidones, polymersderived from acrylic acid and methacrylic acid and salts thereof, oraminoacid polymers, or a mixture of 2 or 3 hyrdophilic polymers chosenfrom the same family wherein (a) and (b) are included in the same layer[(a)+(b)] or in separate layers ](a)[ and [(b)] and wherein multiplelayers containing (a), (b) or (a) and (b) in the same tablet have thesame or different compositions and dimensions, and (c) a hydrophilicexcipient capable of promoting the hydration of swelling polymermatrices, chosen from lactose, mannitol, sorbitol, microcrystallinecellulose, sodium lauryl sulfate, sodium ricinoleate, sodium tetradecylsulfate, sodium dioctyl sulfosulfonate, ketomagrocol, poloxamer andpolysorbates.
 2. A composition according to claim 1 wherein the carbondioxide-generating system comprises at least one carbondioxide-generating agent chosen from an alkali metal carbonate, analkaline-earth metal carbonate and an alkali metal bicarbonate.
 3. Acomposition according to claim 2 wherein the carbon dioxide-generatingsystem comprises at least one carbon dioxide-generating agent and atleast one acidic compound chosen from the group consisting ofmonocarboxylic acids, polycarboxylic acids and partial salts ofpolycarboxylic acids.
 4. A composition according to claim 3 wherein theacidic compound is tartaric acid, succinic acid, citric acid or apartial salt thereof.
 5. A composition according to claim 4 wherein theactive principle is a benzamide.
 6. A composition according to claim 4wherein the active principle is an α₁-antagonist.
 7. A compositionaccording to claim 4 wherein the active principle is captopril,furosemide, ursodeoxycholic acid, amoxicillin,(+)-α-aminomethyl-2-methoxy-5-sulfonamidobenzenemethanol or3′-(2-amino-1-hydroxyethyl)-4′-fluoromethanesulfonanilide, or a saltthereof.
 8. A composition according to claim 4 wherein the activeprinciple is selected from the group consisting of amisulpride(D)-tartrate, (S)-(−)-amisulpride, (S)-(−)-amisulpride (D)-tartrate,tiapride hydrochloride, alfuzosine hydrochloride and3′-(2-amino-1-hydroxyethyl)4′-fluoromethanesulfonanilide hydrochloride.9. A composition according to claim 1 wherein the active principle is abenzamide.
 10. A composition according to claim 1 wherein the activeprinciple is an α₁-antagonist.
 11. A composition according to claim 1wherein the active principle is captopril, furosemide, ursodeoxycholicacid, amoxicillin,(+)-α-aminomethyl-2-methoxy-5-sulfonamidobenzenemethanol or3′-(2-amino-1-hydroxyethyl)-4′-fluoromethanesulfonanilide, or a saltthereof.
 12. A composition according to claim 1 wherein the activeprinciple is selected from the group consisting of amisulpride(D)-tartrate, (S)-(−)-amisulpride, (S)-(−)-amisulpride (D)-tartrate,tiapride hydrochloride, alfuzosine hydrochloride and3′-(2-amino-1-hydroxyethyl)4′-fluoromethanesulfonanilide hydrochloride.13. A composition according to claim 1 wherein the excipient whichmodifies the release of the active principle is a hydrophilic polymerchosen from the following families of hydrophilic polymers: naturalpolysaccharides, cellulose derivatives, polyvinylpyrrolidones, polymersderived from acrylic acid and methacrylic acid and salts thereof, oraminoacid polymers, or a mixture of 2 or 3 hydrophilic polymers chosenfrom the same family, or, when (a) and (b) are in separate layers, saidexcipient may further be a lipid substance chosen from hydrogenatedcastor oil, beeswax, carnauba wax, glyceryl trimyristate, glyceryltrilaurate, glyceryl tristearate, cetyl palmitate and glyceryl behenate,or a combination of a hydrophilic polymer and a lipid substance.
 14. Acomposition according to claim 13 wherein the carbon dioxide-generatingsystem comprises at least one carbon dioxide-generating agent which maybe chosen from an alkali metal carbonate or alkaline-earth metalcarbonate and an alkali metal bicarbonate.
 15. A composition accordingto claim 14 wherein the carbon dioxide-generating system comprises atleast one carbon dioxide-generating agent and at least one acidiccompound chosen from the group consisting of monocarboxylic acids,polycarboxylic acids and partial salts of polycarboxylic acids.
 16. Acomposition according to claim 15 wherein the acidic compound istartaric acid, succinic acid, citric acid or a partial salt thereof. 17.A composition according to claim 16 wherein the active principle is abenzamide.
 18. A composition according to claim 16 wherein the activeprinciple is an α₁-antagonist.
 19. A composition according to claim 16wherein the active principle is captopril, furosemide, ursodeoxycholicacid, amoxicillin,(+)-α-aminomethyl-2-methoxy-5-sulfonamidobenzenemethanol or3′-(2-amino-1-hydroxyethyl)-4′-fluoromethanesulfonanilide, or a saltthereof.
 20. A composition according to claim 16 wherein the activeprinciple is selected from the group consisting of amisulpride(D)-tartrate, (S)-(−)-amisulpride, (S)-(−)-amisulpride (D)-tartrate,tiapride hydrochloride, alfuzosine hydrochloride and3′-(2-amino-1-hydroxyethyl)-4′-fluoromethanesulfonanilide hydrochloride.21. A composition according to claim 1 wherein the hydrophilic polymeris chosen from alginates, xantham gum, guar gum, gum arabic or carobgum, methylhydroxyethylcellulose, carboxymethylcellulose, sodiumcarboxymethylcellulose, calcium carboxymethylcellulose,hydroxypropylcellulose or hydroxypropylmethylcellulose, polyacrylates,or polylysines.
 22. A composition according to claim 21 wherein theexcipient which modifies the release of the active principle is ahydrophilic polymer chosen from the following families of hydrophilicpolymers: natural polysaccharides, cellulose derivatives,polyvinylpyrrolidones, polymers derived from acrylic acid andmethacrylic acid and salts thereof, or aminoacid polymers, or a mixtureof 2 or 3 hydrophilic polymers chosen from the same family, or, when (a)and (b) are in separate layers, said excipient may further be a lipidsubstance chosen from hydrogenated castor oil, beeswax, carnauba wax,glyceryl trimyristate, glyceryl trilaurate, glyceryl tristearate, cetylpalmitate and glyceryl behenate, or a combination of a hydrophilicpolymer and a lipid substance.
 23. A composition according to claim 22wherein the carbon dioxide-generating system comprises at least onecarbon dioxide-generating agent chosen from an alkali metal carbonate oralkaline-earth metal carbonate and an alkali metal bicarbonate.
 24. Acomposition according to claim 23 wherein the carbon dioxide-generatingsystem comprises at least one carbon dioxide-generating agent and atleast one acidic compound chosen from the group consisting ofmonocarboxylic acids, polycarboxylic acids and partial salts ofpolycarboxylic acids.
 25. A composition according to claim 24 whereinthe acidic compound is tartaric acid, succinic acid, citric acid or apartial salt thereof.
 26. A composition according to claim 25 whereinthe active principle is a benzamide.
 27. A composition according toclaim 25 wherein the active principle is an α₁-antagonist.
 28. Acomposition according to claim 25 wherein the active principle iscaptopril, furosemide, ursodeoxycholic acid, amoxicillin,(+)-α-aminomethyl-2-methoxy-5-sulfonamidobenzenemethanol or3′-(2-amino-1-hydroxyethyl)-4′-fluoromethanesulfonanilide, or a saltthereof.
 29. A composition according to claim 25 wherein the activeprinciple is selected from the group consisting of amisulpride(D)-tartrate, (S)-(−)-amisulpride, (S)-(−)-amisulpride (D)-tartrate,tiapride hydrochloride, alfuzosine hydrochloride and3′-(2-amino-1-hydroxyethyl)-4′-fluoromethanesulfonanilide hydrochloride.